The continuing human health toll of tobacco use has prompted the public health community to evaluate harm reduction approaches. The FTC-based machine-smoke yield measurements promoted by the tobacco industry for their products do not account for differences in human smoking behavior and therefore are not reliable indicators of the harm reduction of potential reduced exposure tobacco products (PREPs). Our long- range goal is to provide the public health community with the technology for ensuring a scientific basis for ultimately judging the effects of PREPs. Mainstream cigarette smoke is a complex mixture of organics that occur free in the gas phase and as higher molecular weight compounds bound to aerosol particles. Potent carcinogens-tobacco-specific nitrosamines and polycyclic aromatic hydrocarbons-occur primarily in the particle phase. Larger particles deposit in the upper part of the respiratory tract;ultrafine particles deposit in deeper parts of the respiratory tract, with longer clearance times and possible health implications. Current techniques can monitor the short half-life tobacco toxins in the gas phase, but are unsuitable for analyzing the aerosol particles, which have much longer half-lives. There has been no work done to date to link particle size and chemical composition of the particles in mainstream smoke. Therefore the aims of this study are: Aim 1: Determine the effect of differences in cigarette and PREP tar levels on changes in particle size distribution and concentration, and on the uptake of mainstream smoke particles by smokers. Aim 2: Determine the effect of differences in cigarette and PREP tar levels on the uptake of selected particle-bound carcinogens from mainstream smoke by smokers. We propose to test 45 subjects who will each smoke one of four designated conventional cigarette brands and two PREPs in six separate test sessions. To obtain an objective measure of their relative toxicity, we will measure and collect the size-fractionated material in smokers'exhaled breath and use simultaneously recorded smoking topography obtained from each smoked cigarette to simulate the individual smoker's inhaled breath dose from the specific puff profile. We will also use chemical characterization procedures we recently developed to measure the unchanged parent compounds and metabolites of the selected smoke carcinogens attached to both the simulated inhaled and the exhaled breath particulate.